The present invention relates generally to cardiopulmonary resuscitation, i.e., restoration of a patient""s respiration and blood circulation following cardiac arrest. More particularly, the invention relates to a method for enhancing cardiopulmonary resuscitation by systemic administration of an xcex12-adrenergic receptor agonist. The invention finds utility in the areas of pharmacology, cardiology and general medicine.
In cardiac arrest, a patient""s heart ceases its normal pumping action and frequently devolves into ventricular fibrillation. Without restoration of circulation, death from anoxia is rapid. Cardiac arrest is a major cause of death and can arise from a variety of circumstances, including heart disease, electric shock and other trauma, suffocation, and the like. To improve the likelihood of patient survival and reduce the likelihood of damage to the brain and heart resulting from oxygen deprivation, it is essential that a patient""s respiration and blood circulation be restored as soon as possible. A number of resuscitation techniques have been developed with the aforementioned objectives in mind.
Generally, cardiopulmonary resuscitation (CPR) techniques are used that rely on external chest compression. Standardized cardiopulmonary restoration (CPR) techniques are described in xe2x80x9cGuidelines for CPR and Emergency Cardiac Care,xe2x80x9d J. Am. Med. Assoc. 268:2205-2211 (1992), which sets out in detail the recommended procedures for administration of drugs and physical intervention in CPR. Manual CPR techniques rely on the application of a downward force on the patient""s chest in order to force blood from the heart and expel air from the lungs. Ventilation by either mouth-to-mouth or mechanical techniques is performed concurrently with chest compression in order to force air back into the patient""s lungs. Such manual CPR techniques, however, rely in large part on the natural elasticity of the chest in order to actively draw venous blood back into the heart, which is generally inefficient. Long-term survival in cardiac arrest patients who have undergone manual CPR is usually below 10%.
An improved CPR method is referred to as active compression/decompression (ACD) CPR. The ACD CPR technique results in improved blood circulation through the heart and ventilation of the patient""s lungs when compared to standard CPR techniques. ACD CPR combines external cardiac compression with active expansion of the patient""s chest after each compression in order to lower intrathoracic pressure and facilitate refilling of the heart. ACD CPR is generally performed with a commercially available device such as the CardioPump, available from Ambu International A/S (Copenhagen). Such devices involve use of a vacuum cup that is applied to the anterior chest wall of the patient, and is used to enable active expansion of the patient""s chest after each compression, to expand the thorax and heart.
Another alternative procedure for inducing blood transport and lung ventilation is known as xe2x80x9cmast trouserxe2x80x9d ventilation, which is performed by placing the patient""s lower extremities in inflatable trousers, which are then inflated to force blood into the thorax and heart. An additional technique involves xe2x80x9cvestxe2x80x9d cardiovascular resuscitation in which the patient is placed in a vest or the like that is capable of pressurizing the chest to expel blood from the thorax.
ACD CPR and other enhanced CPR methods have been established to improve the chances for patient survival relative to conventional CPR. However, it would be desirable if the chances of patient survival could be increased even further.
To this end, advanced cardiac life support (ACLS) techniques have been developed. Such techniques typically include the intravenous or endotracheal administration of fluids and pharmacological agents during performance of CPR. A review of the pharmacological agents that are generally administered in conjunction with cardiopulmonary resuscitation can be found in Otto (December 1986), Cir. 74 (supplement IV), IV-80-85.
Rapid restoration of coronary perfusion and therefore myocardial blood flow is the overriding determinant of the success of CPR during cardiac arrest. It provides a rationale for the widespread use of adrenergic vasopressor agents and especially epinephrine. J. Am. Med. Assoc. 268:2205-2211 (1992), cited supra. Increases in arterial resistance enhance aortic diastolic pressure, coronary perfusion pressure and myocardial blood flow during either closed-chest precordial compression, as described above, or open chest cardiac massage. The success of electrical defibrillation is contingent upon restoring threshold levels of myocardial blood flow after prolonged cardiac arrest. Duggal et al. (1993), xe2x80x9cRegional Blood Flow During Closed Chest Cardiac Resuscitation in Rats,xe2x80x9d J. Appl. Physiol. 74:147-152.
Epinephrine has been the preferred adrenergic agent for the treatment of human cardiac arrest for almost 30 years. When vasopressor agents with P-adrenergic actions, like epinephrine, are administered to enhance coronary perfusion during CPR, however, xcex2-adrenergic effects simultaneously increase myocardial oxygen requirements. Ditchey et al. (1988), xe2x80x9cFailure of Epinephrine to Improve the Balance Between Myocardial Oxygen Supply and Demand During Closed-Chest Resuscitation in Dogs,xe2x80x9d Circulation 78:382-389; Ditchey et al. (1989), xe2x80x9cPhenylephrine plus Propranolol Improves Myocardial Oxygenation During CPR,xe2x80x9d Circulation 80:492-494. Consequently, epinephrine can increase the severity of post-resuscitation myocardial dysfunction and decrease the rate of survival. Tang et al. (1993), xe2x80x9cProgressive Myocardial Dysfunction After Cardiac Resuscitation,xe2x80x9d Crit. Care Med. 21:1046-1050; Tang et al. (1995), xe2x80x9cEpinephrine Increases the Severity of Post-Resuscitation Myocardial Dysfunction,xe2x80x9d Circulation 92:3089-3093.
The xcex2-adrenergic effects of epinephrine also alter the distribution of pulmonary blood flow and thereby produce ventilation/perfusion abnormalities such that they induce an increase in the arterial partial pressure of carbon dioxide (PCO2) and a decrease in the arterial partial pressure of oxygen (PO2). In one study, end tidal CO2 (ETCO2) was found to decrease by 50% immediately following administration of epinephrine both under physiological conditions of spontaneous circulation and during CPR. Tang et al. (1991), xe2x80x9cPulmonary Ventilation/Perfusion Defects Induced by Epinephrine During Cardiopulmonary Resuscitation,xe2x80x9d Circulation 84:2101-2107; Cantineau et al. (1994), xe2x80x9cEffect of Epinephrine on End-Tidal Carbon Dioxide Pressure During Prehospital Cardiopulmonary Resuscitation,xe2x80x9d Am. J. Emerg. Med. 12:267-270. The xcex2-adrenergic effects of epinephrine also increase the risk of re-entrant and ectopic ventricular dysrhythmias after successful resuscitation, issues that may be of even greater importance when high doses of epinephrine are administered. Brown et al. (1992), xe2x80x9cA Comparison of Standard-Dose and High-Dose Epinephrine in Cardiac Arrest Outside the Hospital,xe2x80x9d N. Engl. J. Med. 327:1051-1055; Stiell et al. (1992), xe2x80x9cHigh-Dose Epinephrine in Adult Cardiac Arrest,xe2x80x9d N. Engl. J. Med. 327:1045-1050.
Predominant xcex11-adrenergic agents such as phenylephrine and methoxamine were found to be as effective as epinephrine for restoring spontaneous circulation. Tang et al. (1991), supra; Tang et al. (1995), supra. However, the inotropic effects of these agents increase myocardial oxygen consumption during cardiac arrest and therefore increase the severity of post-resuscitation myocardial dysfunction. Rapid desensitization of presynaptic xcex11-adrenergic receptors during ischemia, especially when the duration of untreated cardiac arrest is prolonged, reduces the potency the xcex11-adrenergic agent administered.
It would therefore be desirable to provide an improved method for cardiopulmonary resuscitation wherein coronary perfusion pressure and therefore myocardial blood flow is rapidly restored, the incidence of post-resuscitation ventricular arrhythmias is minimized, the severity of post-resuscitation myocardial dysfunction is decreased, and the overall likelihood of patient survival is increased.
Accordingly, it is a primary object of the invention to address the above-described need in the art by providing a method for enhancing the efficacy of cardiopulmonary resuscitation and minimizing post-resuscitation myocardial dysfunction.
It is another object of the invention to provide such a method by administering an xcex12-adrenergic receptor agonist to a patient following cardiac arrest, during or subsequent to performing cardiopulmonary resuscitation procedures.
It is another object of the invention to provide such a method wherein the active agent administered is a selective xcex12-adrenergic receptor agonist.
It is an additional object of the invention to provide such a method wherein the active agent administered is xcex1-methylnorepinephrine.
It is a further object of the invention to provide a kit for conducting the therapeutic methods described and claimed herein.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one embodiment, a method is provided for enhancing the efficacy of cardiopulmonary resuscitation, i.e., for increasing the likelihood of patient survival, decreasing the severity of post-resuscitation myocardial dysfunction, and reducing the incidence of post-resuscitation ventricular arrhythmias. The method comprises administering an xcex12-adrenergic receptor agonist to a patient following cardiac arrest, in combination with conventional or enhanced cardiopulmonary resuscitation procedures. The preferred active agents are xcex12-adrenergic receptor agonists that do not cross the blood-brain barrier, and particularly preferred active agents within this group are selective xcex12-adrenergic receptor agonists such as xcex1-methylnorepinephrine. These active agents cause vasoconstriction and therefore raise aortic pressure to restore coronary perfusion and thereby myocardial blood flow without the detriment of inotropic or chronotropic actions during and following cardiopulmonary resuscitation.
In another embodiment, a kit is provided for carrying out the aforementioned therapeutic method, wherein the kit comprises: a pharmaceutical formulation comprising an xcex12-adrenergic receptor agonist as described herein; a closed container housing the formulation; a means for administering the formulation to a patient; and instructions for administering the formulation to enhance the efficacy of cardiopulmonary resuscitation following cardiac arrest.